Magnolol alleviates hypoxia-induced pulmonary vascular remodeling through inhibition of phenotypic transformation in pulmonary arterial smooth muscle cells.

Phenotypic transformation and excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) play an important role in vascular remodeling during pulmonary hypertension (PH). Magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) is the major bioactive constituent isolated from the bark of Magnolia Officinalis, which has anti-inflammatory, antioxidant, and cardiovascular protection effects. However, the effect of magnolol on the phenotypic transformation of PASMCs is still unknown. This study aims to evaluate the effects of magnolol on the phenotypic transformation of PASMCs induced by hypoxia. In vivo, Sprague Dawley rats were exposed to hypoxia (10% O2) for four weeks to establish a PH model. The results showed that hypoxia treatment led to an increase in right ventricle systolic pressure, Fulton index, collagen production, accompanied by upregulation in the expression of collagen Ⅰ, collagen Ⅲ, OPN, PCNA, CyclinD1, p-JAK2, and p-STAT3, as well as decreases in expression of SM-22α; these changes were attenuated by magnolol. In vitro, the primary cultured PASMCs were exposed to 3% O2 for 48 h to induce phenotypic transformation. Consistent with the findings in vivo, magnolol treatment could prevent the phenotypic transformation and hyperproliferation of PASMCs induced by hypoxia, accompanied by downregulation in the expression of p-JAK2 and p-STAT3. In summary, this study demonstrated that the protective effect of magnolol on PH vascular remodeling is related to the inhibition of phenotypic transformation and hyperproliferation of PASMCs by inhibiting the JAK2/STAT3 pathway.

Alkaloids and phenylpropanoid from Rhizomes of Arundo donax L.

A new bis-indole alkaloid, named arundaline (1), a new phenylpropanoid, named arundalcohol (2), and four known alkaloids, N-acetyltryptamine (3), trans-N-(p-coumaroyl)serotonin (4), trans-N-feruloylserotonin (5), and tuberosine B (6), were isolated from 70% aqueous ethanol extracts of the rhizomes of Arundo donax L. Their structures were elucidated by spectroscopic analysis and comparison of the data with literature values. Compounds 3-6 were isolated from the genus Arundo for the first time.

miR-29a Negatively Affects Glucose-Stimulated Insulin Secretion and MIN6 Cell Proliferation via Cdc42/ß-Catenin Signaling.

BACKGROUND: Diabetes is a progressive metabolic disease characterized by hyperglycemia. Functional impairment of islet ß cells can occur to varying degrees. This impairment can initially be compensated for by proliferation and metabolic changes of ß cells. Cell division control protein 42 (Cdc42) and the microRNA (miRNA) miR-29 have important roles in ß-cell proliferation and glucose-stimulated insulin secretion (GSIS), which we further explored using the mouse insulinoma cell line MIN6. METHODS: Upregulation and downregulation of miR-29a and Cdc42 were accomplished using transient transfection. miR-29a and Cdc42 expression was detected by real-time PCR and western blotting. MIN6 proliferation was detected using a cell counting kit assay. GSIS under high-glucose (20.0 mM) or basal-glucose (5.0 mM) stimulation was detected by enzyme-linked immunosorbent assay. The miR-29a binding site in the Cdc42 mRNA 3'-untranslated region (UTR) was determined using bioinformatics and luciferase reporter assays. RESULTS: miR-29a overexpression inhibited proliferation (P < 0.01) and GSIS under high-glucose stimulation (P < 0.01). Cdc42 overexpression promoted proliferation (P < 0.05) and GSIS under high-glucose stimulation (P < 0.05). miR-29a overexpression decreased Cdc42 expression (P < 0.01), whereas miR-29a downregulation increased Cdc42 expression (P < 0.01). The results showed that the Cdc42 mRNA 3'-UTR is a direct target of miR-29a in vitro. Additionally, Cdc42 reversed miR-29a-mediated inhibition of proliferation and GSIS (P < 0.01). Furthermore, miR-29a inhibited ß-catenin expression (P < 0.01), whereas Cdc42 promoted ß-catenin expression (P < 0.01). CONCLUSION: By negatively regulating Cdc42 and the downstream molecule ß-catenin, miR-29a inhibits MIN6 proliferation and insulin secretion.

Notch and breast cancer metastasis: Current knowledge, new sights and targeted therapy.

Breast cancer is the most common type of invasive cancer in females and metastasis is one of the major causes of breast cancer-associated mortality. Following detachment from the primary site, disseminated tumor cells (DTCs) enter the bloodstream and establish secondary colonies during the metastatic process. An increasing amount of studies have elucidated the importance of Notch signaling in breast cancer metastasis; therefore, the present review focuses on the mechanisms by which Notch contributes to the occurrence of breast cancer DTCs, increases their motility, establishes interactions with the tumor microenvironment, protects DTCs from host surveillance and finally facilitates secondary colonization. Identification of the underlying mechanisms of Notch-associated breast cancer metastasis will provide additional insights that may contribute towards the development of novel Notch-targeted therapeutic strategies, which may aid in reducing metastasis, culminating in an improved patient prognosis.

Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases.

Cdc42, a member of the Rho GTPases family, is involved in the regulation of several cellular functions including cell cycle progression, survival, transcription, actin cytoskeleton organization and membrane trafficking. Diabetes is a chronic and metabolic disease, characterized as glycometabolism disorder induced by insulin deficiency related to ß cell dysfunction and peripheral insulin resistance (IR). Diabetes could cause many complications including diabetic nephropathy (DN), diabetic retinopathy and diabetic foot. Furthermore, hyperglycemia can promote tumor progression and increase the risk of malignant cancers. In this review, we summarized the regulation of Cdc42 in insulin secretion and diabetes-associated diseases. Organized researches indicate that Cdc42 is a crucial member during the progression of diabetes, and Cdc42 not only participates in the process of insulin synthesis but also regulates the insulin granule mobilization and cell membrane exocytosis via activating a series of downstream factors. Besides, several studies have demonstrated Cdc42 as participating in the pathogenesis of IR and DN and even contributing to promote cancer cell proliferation, survival, invasion, migration, and metastasis under hyperglycemia. Through the current review, we hope to cast light on the mechanism of Cdc42 in diabetes and associated diseases and provide new ideas for clinical diagnosis, treatment, and prevention.

Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/ß-Catenin Signaling.

PURPOSE: Type 1 diabetes mellitus (T1DM) is characterized by irreversible islet ß cell destruction. Accumulative evidence indicated that Cdc42 and Wnt/ß-catenin signaling both play a critical role in the pathogenesis and development of T1DM. Further, bio-molecular mechanisms in adipose-derived mesenchymal stem cells (ADSCs)-derived insulin-producing cells (IPCs) remain largely unknown. Our aim was to investigate the underlying mechanism of Cdc42/Wnt/ß-catenin pathway in ADSC-derived IPCs, which may provide new insights into the therapeutic strategy for T1DM patients. METHODS: ADSC induction was accomplished with DMSO under high-glucose condition. ML141 (Cdc42 inhibitor) and Wnt-3a (Wnt signaling activator) were administered to ADSCs from day 2 until the induction finished. Morphological changes were determined by an inverted microscope. Dithizone staining was employed to evaluate the induction of ADSC-derived IPCs. qPCR and Western blotting were employed to measure the mRNA and protein expression level of islet cell development-related genes and Wnt signaling-related genes. The proliferation ability of ADSC-derived IPCs was also detected with a cell counting kit (CCK) assay. The expression and secretion of Insulin were detected with immunofluorescence test and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: During induction, morphological characters of ADSCs changed into spindle and round shape, and formed islet-line cell clusters, with brown dithizone-stained cytoplasm. Expression levels of islet cell development-related genes were up-regulated in ADSC-derived IPCs. Wnt-3a promoted Wnt signaling markers and islet cell development-related gene expression at mRNA and protein levels, while ML141 played a negative effect. Wnt-3a promoted ADSC-derived IPC proliferation and glucose-stimulated insulin secretion (GSIS), while ML141 played a negative effect. CONCLUSION: Our research demonstrated that DMSO and high-glucose condition can induce ADSCs into IPCs, and Wnt signaling promotes the induction. Cdc42 may promote IPC induction, IPC proliferation and insulin secretion via Wnt/ß-catenin pathway, meaning that Cdc42 may be regarded as a potential target in the treatment of T1DM.

Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates.

Despite great improvements in the diagnosis and treatment of neoplasms, metastatic disease is still the leading cause of death in cancer patients, with mortality rates still rising. Given this background, new ways to treat cancer will be important for development of improved cancer control strategies. Cdc42 is a member of the Rho GTPase family and plays an important role in cell-to-cell adhesion, formation of cytoskeletal structures, and cell cycle regulation. It thus influences cellular proliferation, transformation, and homeostasis, as well as the cellular migration and invasion processes underlying tumor formation. Cdc42 acts as a collection point for signal transduction and regulates multiple signaling pathways. Moreover, recent studies show that in most human cancers Cdc42 is abnormally expressed and promoting neoplastic growth and metastasis. Regarding possible new treatments for cancer, miRNA and small molecules targeting Cdc42 and related pathways have been recently found to be effective on cancer. In this review, we analyze the newly recognized regulation mechanisms for Cdc42 and Cdc42-related signal pathways, and particularly new treatments using small molecules and miRNAs to inhibit the abnormal overexpression of Cdc42 that may slow down the metastasis process, improve cancer therapy and lead to novel strategies for development of antineoplastic drugs.